Registration Dossier

Administrative data

Description of key information

Available studies on the acute irritation potential of fatty acid methyl esters neither showed irritating potential to human skin nor eye irriation potential to the eye in vivo.

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for grouping of substances and read-across

The short chain methyl esters category (SCAE Me) covers fatty acid esters of methanol. The category contains both mono-constituent substances, with fatty acid C-chain lengths ranging from C6 to C18 and UVCB substances, composed of single methyl esters in variable proportions. 

The available data allows for an accurate hazard and risk assessment of the category and the category concept is applied for the assessment of environmental fate, environmental and human health hazards. Thus where applicable, environmental and human health effects are predicted from adequate and reliable data for source substance(s) within the group by interpolation to the target substances in the group (read-across approach) applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. In particular, for each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Sections 7.1 and 13) and within Chapter 5.1 of the CSR.

Table: Endpoint Skin irritation

CAS

 

Skin irritation

106-70-7 (a)

Experimental result: not irritating to human and rabbit skin

111-11-5

Experimental result: not irritating to human skin

110-42-9

Experimental result: not irritating to human skin

111-82-0

Experimental result: not irritating to human skin

124-10-7 (b)

Experimental result: not irritating to human skin

112-39-0

Experimental result: not irritating to human skin

112-61-8

Experimental result: not irritating to rabbit skin

112-62-9

Experimental result: not irritating to human skin

85566-26-3

RA: 111-11-5 and 110-42-9: not irritating to human skin

308065-15-8

RA: 111-82-0: not irritating to human skin

1234694-02-0

RA: 111-82-0 and 112-39-0: not irritating to human skin

RA: 67762-38-3: not irritating to rabbit skin

85586-21-6

RA: 112-39-0 and 112-62-9: not irritating to human skin

RA: 67762-38-3: not irritating to rabbit skin

67762-38-3

Experimental result: not irritating to rabbit skin

67762-26-9

 

Experimental result: not irritating to human and rabbit skin

(a) Category members subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font.

(b) Substances that are either already registered under REACh or not subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in normal font.

For all category members registered under REACh a full data set for each endpoint is provided. For substances not subject to the current REACh Phase-in registration, lack of data for a given endpoint is indicated by "--".

Skin irritation - Human Data

Several fatty acid methyl esters were tested in vivo on human skin. None of the tested fatty acid methyl esters showed any relevant skin irritation potential on human skin:

 

A reliable human volunteer study was performed (Kremer, 1998) to investigate the skin irritation potential of methyl caproate (C6, CAS No. 106-70-7), methyl caprylate (C8, CAS No. 111-11-5), methyl decanoate (C10, CAS No. 110-42-9), methyl laurate (C12, CAS No. 111-82-0), methyl myristate (C14, CAS No. 124-10-7), methyl palmitate (C16, CAS No. 112-39-0) and methyl oleate (CAS No. 112-62-9). Different fatty acid methyl esters were tested in 20 human volunteers for their skin irritation potential according to COLIPA (4 h human patch test) under GCP conditions. The dorsal skin was exposed to 70 μL of the undiluted test substances for 24 hours under occlusive conditions using Finn Chambers on Scanpor. Reference substances including Texapon N28 (tenside standard with good skin compatibility), sodium-dodecylsulfate, cosmetic alcohol, physiological saline and paraffin oil were tested concurrently. Sites were assessed for skin reactions (i.e., erythema, oedema, eschar and fissure formations) 6, 24, 48 and 72 hours after patch removal according to the system of Frosch and Kligman (1979). The skin compatibility towards methyl caproate (C6) was comparable with taht of Texapon N 28 and thus found to be satisfying. Good skin compatibility was found towards methyl caprylate (C8), methyl decanoate (C10), methyl laurate (C12), methyl myristate (C14) and methyl palmitate (C16). Very good skin compatibility was found for methyl oleate (C18). The 4 hour testing method under occlusive conditions in 20 human volunteers was found to be sufficient for hazard assessment of the tested substances.

 

Another human volunteer study was performed (Krächter 1994) to investigate the skin irritation potential of methyl laurate (C12, CAS No. 111-82-0). 60 healthy volunteers were tested for skin irritation potential of the test material in an open epicutaneous test according to the method described by Burckhard (Burckhard 1964. Dermatologica 129: 37-46). The test material was applied in concentrations of 10 and 20 (20 volunteers), 50 (20 volunteers) and 100% (20 volunteers) onto the skin of the volunteers every 30 sec for a time of overall 30 min on the inside of the forearm of the volunteers under open conditions. None of the volunteers showed any signs of irritation at any concentration tested.

 

In a third human volunteer study (Matthies 1988) the skin irritation potential of methyl palmitate (C16, CAS No. 112-39-0) and fatty acids, C14-C18 and C16-C18 unsaturated, methyl esters (CAS No. 67762-26-9) was investigated. In a modified Duhring-chamber test 20 healthy volunteers were applied 70 µL of a 50 % dilution of the test substance as a single application on the back for 24 h with occlusive patches (i.e. Fin Chamber on Scanpor). There were only very slight reactions observed for erythema, edema, scaling and fissuring. The irritation index of both test materials was much lower than that of the internal standard 1% Texapon N 25 (i.e. positve control). No signs of skin irritation were found.

 

 

Skin irritation - Animal Data

Several fatty acid methyl esters were tested in vivo on rabbit skin. While some of the study results indicated no skin irritation potential, other studies indicated a skin irritation potential in rabbits:

 

CAS 111-82-0 

Two animal studies investigating the skin irritation of methyl laurate are available (CAS 111-82-0). In a primary dermal irritation study, the skin irritation/corrosion potential of methyl laurate (CAS 111-82-0) was tested according to OECD Guideline 404 (Busschers, 1998). The shaved dorsal skin of three male New Zealand White rabbits was exposed to 0.5 mL unchanged test material for 4 hours under semi-occlusive conditions. After exposure remaining test substance was removed with a moistened tissue. The rabbits were observed for 7 days. Skin reactions were assessed using the Draize scheme 1, 24, 48, 72 hours and 7 days after removal of the test substance. The exposure period of four hours resulted in well defined or moderate to severe erythema and moderate oedema in the treated skin-areas of all three rabbits. The skin irritation had resolved within 7 days after exposure in all animals. At the end of the observation period, scaliness was noted in all animals and in addition bald skin at the edges of the application area was noted in two animals.

In another study, the skin corrosion potential of methyl laurate (CAS 111-82-0) was tested according to D.O.T. Corrosivity, 49 CFR 173.240 (Hiles, 1982). 0.5 mL of the unchanged test substance was applied to the shaved back of 6 New Zealand White rabbits for 4 hours under occlusive conditions. The animals were observed for 48 hours. The skin was evaluated for corrosion immediately after patch removal and after 44 h (48 h after application). The test substance caused only slight erythema, which persisted until the end of the observation period. No oedema occurred in any of the 6 tested animals.

 

CAS 112-39-0 

Methyl palmitate (CAS No. 112-39-0) was investigated in a primary skin irritation study according to OECD 404 (Steiling, 1992). The shaved dorsal skin of three Klein-russen rabbits was exposed to 0.5 g unchanged pasty test material for 4 hours under semi-occlusive conditions. After exposure the skin was cleaned from the residual test substance. The rabbits were observed for 21 days. Skin reactions were assessed using the Draize scheme 1, 24, 48, 72 hours as well as 7, 14 and 21 days after removal of the test substance. The exposure period of four hours resulted in strong skin irritation in all animals that persisted as slight erythema in one animal until the end of the observation period of 21 days.

 

CAS 106-70-7 

For methyl hexanoate (CAS No. 106-70-7), a primary skin irritation study was performed according to OECD Guideline 404 under GLP conditions (Pittermann, 1992). The shaved dorsal skin of three Kleinrussen rabbits was exposed to 0.5 mL unchanged test material for 4 hours under semi-occlusive conditions. The rabbits were observed for 22 days. Skin reactions were assessed using the Draize scheme approx. 1, 24, 48, 72 hours as well as 7, 14 and 22 days after removal of the test substance. Slight to weak erythema and oedema were observed in all three animals during the first 72 h after exposure. One week after exposure the skin of one experimental animal showed eschar formation. The observed skin effects were fully reversible within 14 days in two animals. In the third animal slight skin irritation persisted over the whole observation period of 22 days.

 

CAS 112-61-8 

A primary dermal irritation study was performed with methyl stearate (CAS No. 112-61-8) according to OECD Guideline 404 (Steiling, 1992). The shaved dorsal skin of three Klein-russen rabbits was exposed to 0.5 g unchanged test material for 4 hours under semi-occlusive conditions. After exposure the skin was cleaned from the residual test substance. The rabbits were observed for 21 days. Skin reactions were assessed using the Draize scheme approx. 1, 24, 48, 72 hours as well as 7, 14 and 21 days after removal of the test substance. The exposure period of four hours caused slight to moderate skin erythema to all three animals. In one animal a slight erythema persisted until the end of the observation period of 21 days. In two animals the skin irritation was fully reversible within 21 days.

 

CAS 67762-26-9 

Another primary dermal irritation study was performed with Fatty acids, C14-18 and C16-18-unsatd., Methyl esters (CAS No. 67762-26-9) according to OECD Guideline 404 (Kästner, 1988). The shaved dorsal skin of three Kleinrussen rabbits was exposed to 0.5 mL unchanged test material for 4 hours under occlusive conditions. The rabbits were observed for 10 days. Skin reactions were assessed using the Draize scheme 24, 48, 72 hours after removal of the test substance. Slight to weak erythema and oedema were observed in all three animals, which were fully reversible in a time period within 1 - 10 days following patch removal.

 

CAS 67762-38-3 

For fatty acids, C16-18 and C18-unsatd., methyl esters (CAS No. 67762-38-3), a primary dermal irritation study according to OECD Guideline 404 was performed (Steiling, 1992). The shaved dorsal skin of three Kleinrussen rabbits was exposed to 0.5 mL unchanged test material for 4 hours under semi-occlusive conditions. The rabbits were observed for 72 hours. Skin reactions were assessed using the Draize scheme 1, 24, 48, 72 hours after removal of the test substance. The exposure period of four hours under semi-occlusive conditions caused only slight erythema in two out of three animals, which was fully reversible within 72 hours. No oedema occurred in any of the treated skin sites.

CAS 112-63-0 

A primary dermal irritation study was performed with methyl linoleate (CAS 112-63-0) according to OECD guideline 404 (Pittermann, 1992). The shaved dorsal skin of three Kleinrussen rabbits was exposed to 0.5 mL unchanged test material for 4 hours under semi-occlusive conditions. The rabbits were observed for 22 days. Skin reactions were assessed using the Draize scheme 1, 24, 48, 72 hours after removal of the test substance. After a exposure period of 4 hours slight to moderate erythema and oedema were observed in all three animals. All irritation effects were fully reversible within 7 - 22 days following patch removal.

 

  

According to the ECETOC Monograph No. 32, ISSN-0773-6347-32 (Ecetoc, 2002) on the use of Human Data in Hazard Classification for Irritation and Sensitisation, comparative testing with rabbits and human volunteers exhibits clear differences in susceptibility to some classes of irritant substances and preparations, amongst others for short chain fatty acid methyl esters. Human skin is, in general, less affected. This may be related mainly to physiological differences between species.

While a classification for skin irritation for some short chain fatty acid methyl esters would be triggered by the animal it is not considered necessaring on the basis of existing evidence from human patch test studies. Therefore, using a weight of evidence approach, no classification for skin irritation for all substances within the fatty acid methyl esters category is required.

 

 

Eye irritation

 

Table: Endpoint Eye irritation

CAS

 

Eye irritation

106-70-7 (a)

Experimental result: not irritating to rabbit eye in vivo

111-11-5

RA: 106-70-7 and 68937-83-7: not irritating

110-42-9

RA: 106-70-7 and 68937-83-7: not irritating

111-82-0

Experimental result: not irritating to rabbit eye in vivo

112-39-0

Experimental result: not irritating to rabbit eye in vivo

112-61-8

Experimental result: not irritating to rabbit eye in vivo

85566-26-3 (b)

RA: 68937-83-7: not irritating to rabbit eye in vivo

308065-15-8

RA: 111-82-0 and 112-39-0: not irritating to rabbit eye in vivo

68937-83-7

Experimental result: not irritating to rabbit eye in vivo

1234694-02-0

RA: 111-82-0. 67762-26-9 and 112-61-8: not irritating to rabbit eye in vivo

85586-21-6

RA: 112-39-0 and 112-61-8: not irritating to rabbit eye in vivo

67762-26-9

Experimental result: not irritating to rabbit eye in vivo

 

(a) Category members subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font. Only for these substances a full set of experimental results and/or read-across is given.

(b) Substances that are either already registered under REACh or not subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

 

 

Several acute eye irritation studies have been performed in rabbits in vivo. None of the tested fatty acid methyl esters showed eye irritation potential:

 

CAS 111-82-0 

An acute eye irritation study was performed with methyl laurate (CAS 111-82-0) according to OECD Guideline 405 (Steiling, 1992). 0.1 mL of the undiluted test substance was instilled into the conjunctival sac of one eye of three Kleinrussen rabbits. The animals were observed for 72 hours. Eye irritation was scored according to the method of Draize 1, 24, 48 and 72 hours after application. Mild redness of conjunctiva and lacrimation was observed in one out of three tested animals, which was however fully reversible within 72 hours.

 

Methyl laurate (CAS 111-82-0) was tested in another study performed similar to OECD Guideline 405 (Hiles, 1982). 0.1 mL of the unchanged test substance was instilled to the conjunctival sac of one eye of 3 New Zealand White rabbits. At 24 hours after instillation no eye reaction occurred in any of the treated animals. Due to the lack of any eye reaction, the observation period was ended at this time point.

 

CAS 112-39-0 

Methyl palmitate (CAS 112-39-0) was tested for its eye irritation potential according to OECD Guideline 405 (Steiling, 1992). 0.1 mL of the undiluted test substance was instilled into the right conjunctival sac of three Kleinrussen rabbits. The animals were observed for 72 hours. Eye irritation was scored according to the method of Draize 24, 48 and 72 hours after application. Mild redness of conjunctiva was observed in all three tested animals, which was fully reversible within 48 or 72 hours.

 

CAS 106-70-7

An acute eye irritation study was performed with methyl hexanoate (CAS 106-70-7) according to the OECD guideline 405 (BASF 1992). 0.1 mL of the undiluted test substance was instilled into the conjunctival sac of one eye of three Kleinrussen rabbits. The animals were observed for 72 hours. Eye irritation was scored according to the method of Draize 1, 24, 48 and 72 hours after application. Mild redness of conjunctiva and lacrimation was observed in one out of three tested animals, which was fully reversible within 48 and 72 hours.

 

CAS 112-61-8

An acute eye irritation study was performed with methyl stearate (CAS No. 112-61-8) according to OECD Guideline 405 (Steiling, 1992). 0.1 mL (approx. 0.7 g) of the undiluted test substance was instilled into the right conjunctival sac of three Kleinrussen rabbits. The animals were observed for 72 hours. Eye irritation was scored according to the method of Draize 24, 48 and 72 hours after application. Mild redness of conjunctiva was observed in two out of three tested animals, which was fully reversible within 48 and 72 hours.

CAS 68937-83-7

For fatty acids, C6-10, methyl esters (CAS No. 68937-83-7), an eye irritation study according to EU Method B.5 (Kästner, 1988) was performed under GLP conditions. 0.1 mL of the liquid undiluted test substance was instilled into the conjunctival sac of one eye of four Kleinrussen rabbits. The animals were observed for at least 48 hours. Eye irritation was scored according to the method of Draize 24 and 48 hours after application in all four animals. Additionally, in one animal the treated eye was scored 72 hours after application. No reactions were observed on the cornea and the iris of the treated animals. Slight to moderate conjunctival reactions were observed directly after instillation, which disappeared totally within 24 hours after application. All scores were zero at 24 and 48 hour readings in all four animals.

CAS 67762-26-9

Fatty acids, C14-18 and C16-18-unsatd., Methyl esters (CAS No. 67762-26-9) was tested for its eye irritation potential according to OECD Guideline 405 (Kästner, 1988). 0.1 mL of the liquid undiluted test substance was instilled into the conjunctival sac of one eye of four Kleinrussen rabbits. The animals were observed for 72 hours. Eye irritation was scored according to the method of Draize 1, 6, 24, 48 and 72 hours after application. Reactions on cornea and iris were not observed. The conjunctival reactions were slight (redness) and disappeared within 24 hours after application. All eye irritation scores were zero in all tested animals at 24, 48 and 72 hour reading time points.

 

Conclusions:

Taking the collective evidence from available human and animal irritation studies, none of the substances within the SCAE Me category members is considered irritating to skin. Therefore, based on the category approach, no classification for skin irritation for all substances within the SCAE Me category is required.

Several acute eye irritation studies have been performed in rabbits in vivo. None of the tested fatty acid methyl esters showed an eye irritation potential. Therefore, based on the category approach, no classification for eye irritation for all substances within the SCAE Me esters category is required.

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within CSR.

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met.

Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint".

Since the group concept is applied to the members of the SCAE Me category, data will be generated from representative reference substance(s) within the category to avoid unnecessary animal testing. Additionally, once the group concept is applied, substances will be classified and labeled on this basis.

Therefore, based on the group concept, the available data on skin and eye irritation do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.